Costimulation Blockade Alters Germinal Center Responses and Prevents Antibody-Mediated Rejection

• Type of Material: Article
• Authors: Eugenia J Kim, Emory University; Jean Kwun, Emory University; Adriana C Gibby, Emory University; Jung Joo Hong, Emory University; Alton Farris III, Emory University; Neal Iwakoshi, Emory University; Francois Villinger, Emory University; Allan Kirk, Emory University; Stuart Knechtle, Emory University
• Language: English
• Date: 2014-01-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.
• Final Published Version (URL): http://dx.doi.org/10.1111/ajt.12526
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 14
• Issue: 1
• Start Page: 59
• End Page: 69
• Grant/Funding Information: This work was supported by the NIH 1U01AI074635 awarded to S.J.K.; NIH R01AI078775 to F.V.; and collaboration with the Yerkes National Primate Center (Yerkes base grant OD P51POD111).; Reagents used in this study were provided by the Nonhuman Primate Reagent Resource (HHSN272200900037C).
• Keywords: Antibody-mediated rejection; INFECTION; ALEMTUZUMAB; Surgery; B-CELL ACTIVATION; Life Sciences & Biomedicine; CAMPATH-1H; ALLOANTIBODY; germinal center reaction; Science & Technology; T FOLLICULAR HELPER; follicular helper T cells; RHESUS MACAQUES; Transplantation; BELATACEPT; KIDNEY-TRANSPLANT; costimulation blockade; ALLOGRAFT SURVIVAL
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM + B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM + B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4 + CD28 + CD95 + ) as well as PD-1 hi CD4 + T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model. Costimulation blockade with belatacept or the CD40-specific antibody 2C10R4 selectively suppresses the humoral response by regulating follicular helper T cells, and prevents antibody-mediated rejection in a T cell depletion-based nonhuman primate renal transplant model.